{"id":1675,"date":"2021-02-11T12:20:31","date_gmt":"2021-02-11T20:20:31","guid":{"rendered":"http:\/\/mydiabeticsoul.com\/?p=1675"},"modified":"2021-02-11T12:20:31","modified_gmt":"2021-02-11T20:20:31","slug":"stem-cell-news-acute-respiratory-distress-syndrome","status":"publish","type":"post","link":"http:\/\/mydiabeticsoul.com\/?p=1675","title":{"rendered":"Stem Cell News: Acute Respiratory Distress Syndrome"},"content":{"rendered":"<div class=\"rq0escxv l9j0dhe7 du4w35lb j83agx80 cbu4d94t g5gj957u d2edcug0 hpfvmrgz rj1gh0hx buofh1pr n8tt0mok hyh9befq iuny7tx3 ipjc6fyt\">\n<div id=\"article__content\" class=\"col-sm-12 col-md-8 col-lg-8 article__content article-row-left\" tabindex=\"-1\">\n<div class=\"article-citation\">\n<div class=\"rlist coolBar__zone\">\n<div class=\"pb-dropzone\" data-pb-dropzone=\"publicaitonContent-series-title\"><a class=\"citation--logo\" title=\"STEM CELLS Translational Medicine homepage\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/journal\/21576580\"><img decoding=\"async\" id=\"journal-banner-image\" class=\"journal-banner-image\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/pb-assets\/journal-banners\/21576580-1501384806430.jpg\" alt=\"STEM CELLS Translational Medicine\" \/><\/a><\/div>\n<div class=\"doi-access-container clearfix\"><span class=\"primary-heading\">Human Clinical Articles<\/span><\/p>\n<div class=\"doi-access-wrapper\">\n<div class=\"open-access access-type\">\n<div class=\"doi-access\" tabindex=\"0\">Open Access<\/div>\n<\/div>\n<\/div>\n<div class=\"doi-access-wrapper\"><\/div>\n<\/div>\n<h1 class=\"citation__title\">Umbilical cord mesenchymal stem cells for COVID\u201019 acute respiratory distress syndrome: A double\u2010blind, phase 1\/2a, randomized controlled trial<\/h1>\n<div class=\"coolBar__section coolBar--sections\"><a id=\"sections_Ctrl\" class=\"coolBar__ctrl\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\" data-db-target-for=\"sections\" data-db-switch=\"icon-close_thin\">Sections<\/a><\/div>\n<\/div>\n<\/div>\n<div class=\"fixedCoolBar\">\n<nav class=\"coolBar stickybar\">\n<div class=\"stickybar__wrapper coolBar__wrapper clearfix\">\n<div class=\"coolBar__second rlist\">\n<div class=\"coolBar__section coolBar--download PdfLink cloned\"><a class=\"coolBar__ctrl pdf-download\" title=\"ePDF\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/epdf\/10.1002\/sctm.20-0472\"><img decoding=\"async\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/products\/pericles\/releasedAssets\/images\/pdf-icon.png\" alt=\"PDF\" \/>PDF<\/a><\/div>\n<div class=\"relative\"><a id=\"0e406ce9-5c43-4e2d-b741-e0b43d1f1865_Ctrl\" class=\"article-tools__ctrl\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\" data-db-target-for=\"0e406ce9-5c43-4e2d-b741-e0b43d1f1865\" data-db-switch=\"icon-close_thin\"><i class=\"icon-Icon_Tools\"><\/i>Tools<\/a><\/div>\n<div class=\"relative\"><a id=\"share-access__ctrl\" class=\"share-access__ctrl\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\" data-db-target-for=\"dff42abe-4b17-4fe9-a9c5-625405cd1007\" data-db-switch=\"icon-close_thin\"><i class=\"icon-Icon_Share\"><\/i>Share<\/a><\/div>\n<\/div>\n<\/div>\n<\/nav>\n<\/div>\n<div id=\"accessDenialslot\" class=\"accessDenialslot\"><\/div>\n<div class=\"article__body \">\n<article>\n<div class=\"abstract-group\">\n<section id=\"section-1-en\" class=\"article-section article-section__abstract\" lang=\"en\" data-lang=\"en\">\n<h2 id=\"d21359384\" class=\"article-section__header section__title main abstractlang_en main\">Abstract<\/h2>\n<div class=\"article-section__content en main\">\n<p>Acute respiratory distress syndrome (ARDS) in COVID\u201019 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti\u2010inflammatory effects and could yield beneficial effects in COVID\u201019 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC\u2010MSC) infusions in subjects with COVID\u201019 ARDS. A double\u2010blind, phase 1\/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty\u2010four subjects were randomized 1:1 to either UC\u2010MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC\u2010MSC treatment group received two intravenous infusions (at day 0 and 3) of 100\u2009\u00b1\u200920\u2009\u00d7\u200910<sup>6<\/sup> UC\u2010MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24\u2009hours postinfusion). Secondary endpoints included patient survival at 31\u2009days after the first infusion and time to recovery. No difference was observed between groups in infusion\u2010associated AEs. No serious adverse events (SAEs) were observed related to UC\u2010MSC infusions. UC\u2010MSC infusions in COVID\u201019 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC\u2010MSC\u2010treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, <i>P<\/i> =\u2009.015), SAE\u2010free survival (<i>P<\/i> =\u2009.008), and time to recovery (<i>P<\/i> =\u2009.03). UC\u2010MSC infusions are safe and could be beneficial in treating subjects with COVID\u201019 ARDS.<\/p>\n<\/div>\n<\/section>\n<\/div>\n<div class=\"pb-dropzone\" data-pb-dropzone=\"below-abstract-group\"><\/div>\n<section class=\"article-section article-section__full\">\n<section id=\"sct312883-sec-0001\" class=\"article-section__content\">\n<div class=\"paragraph-element\">\n<div id=\"sct312883-blkfxd-0002\" class=\"block-box box\">\n<section id=\"sct312883-sec-0002\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0002-title\" class=\"article-section__title section__title section2\">Lessons learned<\/h2>\n<div class=\"paragraph-element\">\n<ul class=\"unordered-list\">\n<li>Two intravenous infusions of umbilical cord mesenchymal stem cells (UC\u2010MSCs), at a dose of 100 million cells per infusion, given 72\u2009hours apart, are safe in COVID\u201019 patients with acute respiratory distress syndrome.<\/li>\n<li>This double blind randomized controlled trial in 24 subjects demonstrated fewer serious adverse events in the UC\u2010MSC treatment group compared with the control group.<\/li>\n<li>UC\u2010MSC treatment was associated with a significant decrease in a set of inflammatory cytokines involved in the COVID\u201019 \u201ccytokine storm.\u201d<\/li>\n<li>UC\u2010MSC treatment was associated with significantly improved patient survival and time to recovery.<\/li>\n<li>The observed findings strongly support further investigation in a larger trial designed to estimate and establish efficacy.<\/li>\n<\/ul>\n<\/div>\n<\/section>\n<section id=\"sct312883-sec-0003\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0003-title\" class=\"article-section__title section__title section2\">Significance statement<\/h2>\n<p>This study was a double\u2010blind, randomized, controlled, early phase clinical trial of umbilical cord mesenchymal stem cell treatment in 24 subjects with COVID\u201019 acute respiratory distress syndrome. This study demonstrated fewer serious adverse events in the treatment group compared with control. Exploratory efficacy analyses provide evidence of significantly improved patient survival and time to recovery. The observed findings strongly support further investigation in a larger trial designed to estimate and establish efficacy. These observations will inform physicians influencing clinical practice and future research in the fields of acute respiratory distress syndrome, COVID\u201019, and other immune\u2010related disorders.<\/p>\n<\/section>\n<\/div>\n<\/div>\n<\/section>\n<section id=\"sct312883-sec-0004\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0004-title\" class=\"article-section__title section__title section1\">1 INTRODUCTION<\/h2>\n<p>Coronavirus disease 2019 (COVID\u201019), a pneumonia\u2010like disease caused by the virus severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102), reached pandemic proportions in early 2020.<sup><a id=\"sct312883-bib-0001R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0001\" data-tab=\"pane-pcw-references\">1<\/a>, <a id=\"sct312883-bib-0002R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0002\" data-tab=\"pane-pcw-references\">2<\/a><\/sup> A subset of subjects infected by SARS\u2010CoV\u20102 develop severe COVID\u201019 requiring hospitalization.<sup><a id=\"sct312883-bib-0003R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0003\" data-tab=\"pane-pcw-references\">3<\/a>, <a id=\"sct312883-bib-0004R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0004\" data-tab=\"pane-pcw-references\">4<\/a><\/sup> Severe COVID\u201019 is believed to result from hyperinflammation, overactive immune response triggering cytokine storm, and a prothrombotic state, collectively determined as immunothrombosis, all elicited by SARS\u2010CoV\u20102 infection.<sup><a id=\"sct312883-bib-0005R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0005\" data-tab=\"pane-pcw-references\">5<\/a>&#8211;<a id=\"sct312883-bib-0008R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0008\" data-tab=\"pane-pcw-references\">8<\/a><\/sup> Subjects progressing to acute respiratory distress syndrome (ARDS) require high\u2010flow oxygen therapy, intensive care, and frequently, mechanical ventilation.<sup><a id=\"sct312883-bib-0003R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0003\" data-tab=\"pane-pcw-references\">3<\/a>, <a id=\"sct312883-bib-0004R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0004\" data-tab=\"pane-pcw-references\">4<\/a>, <a id=\"sct312883-bib-0009R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0009\" data-tab=\"pane-pcw-references\">9<\/a>&#8211;<a id=\"sct312883-bib-0012R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0012\" data-tab=\"pane-pcw-references\">12<\/a><\/sup> Mortality in patients with COVID\u201019 and ARDS was reported to be 52.4%.<sup><a id=\"sct312883-bib-0010R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0010\" data-tab=\"pane-pcw-references\">10<\/a><\/sup> There is an urgent need for novel therapies that can attenuate the excessive inflammatory response associated with the immunopathological cytokine storm and immunothrombosis, that can accelerate the recovery of functional lung tissue, and that can abate mortality in patients with severe COVID\u201019.<\/p>\n<p>Mesenchymal stem cells, also known as mesenchymal stromal cells or medicinal signaling cells (MSCs),<sup><a id=\"sct312883-bib-0013R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0013\" data-tab=\"pane-pcw-references\">13<\/a><\/sup> have been shown to modulate overactive immune and hyperinflammatory processes, promote tissue repair, and secrete antimicrobial molecules.<sup><a id=\"sct312883-bib-0014R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0014\" data-tab=\"pane-pcw-references\">14<\/a>&#8211;<a id=\"sct312883-bib-0016R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0016\" data-tab=\"pane-pcw-references\">16<\/a><\/sup> These cells, with established safety profile when administered intravenously,<sup><a id=\"sct312883-bib-0017R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0017\" data-tab=\"pane-pcw-references\">17<\/a><\/sup> have been studied for treatment of autoimmune diseases (eg, type 1 diabetes [T1D]),<sup><a id=\"sct312883-bib-0018R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0018\" data-tab=\"pane-pcw-references\">18<\/a>, <a id=\"sct312883-bib-0019R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0019\" data-tab=\"pane-pcw-references\">19<\/a><\/sup> systemic lupus erythematous,<sup><a id=\"sct312883-bib-0020R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0020\" data-tab=\"pane-pcw-references\">20<\/a><\/sup> inflammatory disorders,<sup><a id=\"sct312883-bib-0021R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0021\" data-tab=\"pane-pcw-references\">21<\/a><\/sup> and steroid\u2010refractory graft\u2010vs\u2010host\u2010disease (GvHD).<sup><a id=\"sct312883-bib-0022R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0022\" data-tab=\"pane-pcw-references\">22<\/a><\/sup> MSCs have been reported to limit inflammation and fibrosis in the lungs,<sup><a id=\"sct312883-bib-0023R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0023\" data-tab=\"pane-pcw-references\">23<\/a>, <a id=\"sct312883-bib-0024R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0024\" data-tab=\"pane-pcw-references\">24<\/a><\/sup> and have generated variable yet promising results in ARDS of viral<sup><a id=\"sct312883-bib-0025R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0025\" data-tab=\"pane-pcw-references\">25<\/a><\/sup> and nonviral etiology.<sup><a id=\"sct312883-bib-0026R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0026\" data-tab=\"pane-pcw-references\">26<\/a>&#8211;<a id=\"sct312883-bib-0029R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0029\" data-tab=\"pane-pcw-references\">29<\/a><\/sup> Multiple ongoing trials are now testing MSCs in patients with severe COVID\u201019, and pilot uncontrolled trials have reported promising results.<sup><a id=\"sct312883-bib-0016R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0016\" data-tab=\"pane-pcw-references\">16<\/a>, <a id=\"sct312883-bib-0030R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0030\" data-tab=\"pane-pcw-references\">30<\/a>&#8211;<a id=\"sct312883-bib-0034R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0034\" data-tab=\"pane-pcw-references\">34<\/a><\/sup> MSCs can be isolated and expanded from multiple tissues, including the umbilical cord (UC). UC\u2010MSCs constitute a cell type of choice in cell therapy trials, including for COVID\u201019.<sup><a id=\"sct312883-bib-0015R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0015\" data-tab=\"pane-pcw-references\">15<\/a>, <a id=\"sct312883-bib-0030R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0030\" data-tab=\"pane-pcw-references\">30<\/a>&#8211;<a id=\"sct312883-bib-0035R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0035\" data-tab=\"pane-pcw-references\">35<\/a><\/sup> The experience accumulated thus far indicates that allogeneic UC\u2010MSC administration is safe in a multitude of diseases.<sup><a id=\"sct312883-bib-0036R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0036\" data-tab=\"pane-pcw-references\">36<\/a><\/sup> These cells can be derived from umbilical cords discarded after delivery and quickly expanded to clinically relevant numbers.<sup><a id=\"sct312883-bib-0037R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0037\" data-tab=\"pane-pcw-references\">37<\/a><\/sup> They express low levels of class I and class II human leukocyte antigen, which may reduce alloreactivity.<sup><a id=\"sct312883-bib-0037R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0037\" data-tab=\"pane-pcw-references\">37<\/a><\/sup> Our Current Good Manufacturing Practice (cGMP) manufacturing facility is now scaling up UC\u2010MSC manufacturing to support upcoming multisite clinical trials, where large numbers of cell doses will be required.<\/p>\n<p>The objective of this study was to establish safety and explore efficacy of allogenic UC\u2010MSC infusions in hospitalized patients with ARDS secondary to COVID\u201019. Here we report the results at 1 month of follow\u2010up of a double\u2010blind randomized controlled trial (RCT) testing this cell\u2010based therapy approach.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0005\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0005-title\" class=\"article-section__title section__title section1\">2 MATERIALS AND METHODS<\/h2>\n<section id=\"sct312883-sec-0006\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0006-title\" class=\"article-section__sub-title section2\">2.1 Trial design<\/h3>\n<p>This double\u2010blind, phase 1\/2a randomized controlled trial was an academic, investigator\u2010initiated trial performed at UHealth System\/Jackson Health System (UHS\/JHS), in Miami, Florida. This trial was designed to evaluate safety and explore efficacy endpoints of allogeneic UC\u2010MSCs in patients with COVID\u201019 and ARDS.<\/p>\n<p>Regulatory, ethical, and institutional review board approvals were obtained by the Western Institutional Review Board and UHS\/JHS Human Subject Research Office\/Institutional Review Board in accordance with local institutional requirements.<\/p>\n<p>Additional details are provided in the supplemental online Methods.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0007\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0007-title\" class=\"article-section__sub-title section2\">2.2 Participants<\/h3>\n<p>The trial was conducted in accordance with the principles of the Declaration of Helsinki and consistent with the Good Clinical Practice guidelines of the International Conference on Harmonisation.<\/p>\n<p>Subjects diagnosed with COVID\u201019 ARDS were eligible for inclusion if they met the eligibility criteria listed in Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S1<\/a> within 24\u2009hours of enrollment. The investigations were performed with informed consent.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0008\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0008-title\" class=\"article-section__sub-title section2\">2.3 Randomization<\/h3>\n<p>Twenty\u2010four subjects hospitalized for COVID\u201019 were randomized 1:1 to either UC\u2010MSC treatment (n = 12) or to the control group (n = 12). Patients were assigned to treatment group using a stratified, blocked randomized design.<\/p>\n<p>Additional details are provided in the supplemental online Methods.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0009\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0009-title\" class=\"article-section__sub-title section2\">2.4 Blinding<\/h3>\n<p>The study was double\u2010blinded: neither the patient nor the assessing physician was aware of treatment assignment, and the staff responsible for product administration were blinded to group assignment.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0010\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0010-title\" class=\"article-section__sub-title section2\">2.5 UC\u2010MSC investigational product<\/h3>\n<p>UC\u2010MSCs were manufactured as previously described.<sup><a id=\"sct312883-bib-0038R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0038\" data-tab=\"pane-pcw-references\">38<\/a><\/sup> UC\u2010MSCs were culture\u2010expanded from a previously established and characterized master cell bank (MCB) derived from the subepithelial lining of a UC, collected from a healthy term delivery (kindly provided by Jadi Cell and Amit Patel, M.D.).<sup><a id=\"sct312883-bib-0037R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0037\" data-tab=\"pane-pcw-references\">37<\/a>, <a id=\"sct312883-bib-0039R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0039\" data-tab=\"pane-pcw-references\">39<\/a><\/sup> The MCB and its source tissue were tested according to the applicable U.S. Food and Drug Administration (FDA) regulations and American Association of Blood Banks (AABB) and Foundation for the Accreditation for Cellular Therapy (FACT) standards for cellular therapies.<\/p>\n<p>In preparation for infusion, frozen UC\u2010MSCs were quickly thawed and slowly diluted in Plasma\u2010LyteA supplemented with human serum albumin and heparin (vehicle solution). The final volume of UC\u2010MSC suspension or vehicle solution (control) for infusion was 50\u2009mL. Cell dose (100\u2009\u00b1\u200920\u2009\u00d7\u200910<sup>6<\/sup>), cell viability by trypan blue (&gt;80%), cell surface marker expression by flow cytometric analysis (CD90\/CD105\u2009&gt;\u200995%, CD34\/CD45\u2009&lt;\u20095%), endotoxin (&lt;1.65 EU\/mL), Gram stain (negative), and 14\u2010day sterility (negative) were used as product release criteria. The vehicle solution was tested for 14\u2010day sterility, Gram stain, and endotoxin. The UC\u2010MSC suspension or vehicle solution was infused within 3 hours of preparation for infusion.<\/p>\n<p>Additional details are provided in the supplemental online Methods.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0011\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0011-title\" class=\"article-section__sub-title section2\">2.6 Interventions<\/h3>\n<p>Subjects in the UC\u2010MSC treatment group received two intravenous infusions of 100\u2009\u00b1\u200920\u2009\u00d7\u200910<sup>6<\/sup> UC\u2010MSCs each, in 50\u2009mL vehicle solution containing human serum albumin and heparin, infused over 10 \u00b1\u20095 minutes, at days 0 and 3. Subjects in the control group (n = 12) received two infusions of 50\u2009mL vehicle solution, at day 0 and day 3. Best standard of care was provided in both groups following the current institutional COVID\u201019 guidelines.<\/p>\n<p>Additional details are provided in the supplemental online Methods.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0012\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0012-title\" class=\"article-section__sub-title section2\">2.7 Outcomes<\/h3>\n<section id=\"sct312883-sec-0013\" class=\"article-section__sub-content\">\n<h4 id=\"sct312883-sec-0013-title\" class=\"article-section__sub-title section3\">2.7.1 <i>Primary endpoints<\/i><\/h4>\n<p>Primary endpoints were the following: (a) safety, defined by the occurrence of prespecified infusion\u2010associated adverse events (AEs) within 6 hours from each infusion; (b) cardiac arrest or death within 24\u2009hours postinfusion; and (c) incidence of AEs.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0014\" class=\"article-section__sub-content\">\n<h4 id=\"sct312883-sec-0014-title\" class=\"article-section__sub-title section3\">2.7.2 <i>Secondary endpoints<\/i><\/h4>\n<p>Secondary endpoints included exploratory efficacy defined by clinical outcomes and laboratory testing and mechanistic analyses.<\/p>\n<p>Clinical outcomes included the following: (a) survival at day 28 after treatment; (b) time to recovery, defined as time to discharge or, if the subject was hospitalized, no longer requiring supplemental oxygen and no longer requiring COVID\u201019\u2010related medical care; and (c) AEs, serious AEs (SAEs), and clinical outcomes assessed for 31\u2009days after the first infusion, corresponding to 28\u2009days after the last infusion.<\/p>\n<p>Laboratory testing and mechanistic analyses included the following: (a) viral load by SARS\u2010CoV\u20102 real\u2010time polymerase chain reaction (RT\u2010PCR) in peripheral blood plasma samples and (b) inflammatory cytokines, chemokines, and growth factors in peripheral blood plasma.<\/p>\n<p>Primary and secondary endpoints are presented in detail in the supplemental online Methods.<\/p>\n<\/section>\n<\/section>\n<section id=\"sct312883-sec-0015\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0015-title\" class=\"article-section__sub-title section2\">2.8 Plasma preparation from peripheral blood<\/h3>\n<p>Whole blood was collected from randomized subjects at day 0 (immediately pretreatment) and at day 6 after treatment initiation. Whole blood was collected into EDTA\u2010treated tubes, transferred on ice, and processed for plasma separation within 4 hours. Whole blood was centrifuged at 2000<i>g<\/i> for 15\u2009minutes at 4\u00b0C. The plasma (top fraction) was collected, aliquoted into cryogenic tubes, and stored at \u221280\u00b0C until processing.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0016\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0016-title\" class=\"article-section__sub-title section2\">2.9 Analysis of viral load by SARS\u2010CoV\u20102 RT\u2010PCR<\/h3>\n<p>The RealStar SARS\u2010COV\u20102 RT\u2010PCR kit (Altona Diagnostics GmbH, Hamburg, Germany) was used to detect the SARS\u2010CoV\u20102\u2010specific S gene and quantify the number of copies per mL of plasma. The assay was performed following the manufacturer&#8217;s instruction, using plasma samples collected from the randomized subjects on day 0 and day 6.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0017\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0017-title\" class=\"article-section__sub-title section2\">2.10 Analysis of inflammatory cytokines, chemokines, and growth factors in peripheral blood plasma<\/h3>\n<p>A protein array (RayBio Q\u2010Series, RayBiotech, Peachtree Corners, Georgia) was used to determine plasma levels of a set of inflammatory cytokines, chemokines, and growth factors (granulocyte\u2010macrophage colony\u2010stimulating factor [GM\u2010CSF], interferon [IFN]g, interleukin [IL]\u20102, IL\u20105, IL\u20106, IL\u20107, tumor necrosis factor [TNF]a, TNFb, platelet\u2010derived growth factor [PDGF]\u2010BB, regulated on activation, normal T cell expressed and secreted, RANTES). The assay was performed using plasma samples collected from the randomized subjects on day 0 and day 6. On the processing day, 1 mL of plasma per sample was thawed in a 37\u00b0C water bath and supplemented with 10 \u03bcL of 100\u00d7 Halt Protease and Phosphatase inhibitor cocktail (Thermo Fisher Scientific, Waltham, Massachusetts). Each plasma sample was diluted 1:2 with sample diluent and assayed following the manufacturer&#8217;s instructions. The fluorescent signals were visualized via a laser scanner equipped with a Cy3 wavelength (green channel) and converted to concentrations (pg\/mL) using the standard curve generated per array.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0018\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0018-title\" class=\"article-section__sub-title section2\">2.11 Statistical methods<\/h3>\n<p>Comparisons of AEs, SAEs, demographics, clinical characteristics, comorbidities, and concomitant treatments between the two groups were performed using Fisher&#8217;s exact test and Wilcoxon two\u2010sample tests for categorical and continuous variables, respectively. Survival, survival in absence of SAE (SAE\u2010free survival), and time to recovery were estimated in each group with Kaplan\u2010Meier survival estimates. Log\u2010rank tests were used to compare hazards between groups. For the analyses of viral load, <i>P<\/i> values were calculated using the Wilcoxon rank\u2010sum test on SAS 9.4. The data were nonnormally distributed. For the analyses of inflammatory cytokines, chemokines, and growth factors, group data at a specific day were analyzed via nonparametric unpaired Mann\u2010Whitney <i>t<\/i> test; for the analyses on longitudinal changes in each group, data at day 0 and day 6 were analyzed via nonparametric paired Wilcoxon <i>t<\/i> test.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0019\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0019-title\" class=\"article-section__sub-title section2\">2.12 Registration<\/h3>\n<p>This trial was registered with <a class=\"linkBehavior\" href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/a> identifier NCT04355728 (<a class=\"linkBehavior\" href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04355728?term=NCT04355728%26draw=2%26rank=1\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04355728?term=NCT04355728&amp;draw=2&amp;rank=1<\/a>).<\/p>\n<\/section>\n<section id=\"sct312883-sec-0020\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0020-title\" class=\"article-section__sub-title section2\">2.13 Clinical trial protocol<\/h3>\n<p>The clinical trial protocol is included in the <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">Data S1<\/a>.<\/p>\n<\/section>\n<\/section>\n<section id=\"sct312883-sec-0021\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0021-title\" class=\"article-section__title section__title section1\">3 RESULTS<\/h2>\n<section id=\"sct312883-sec-0022\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0022-title\" class=\"article-section__sub-title section2\">3.1 Participant flow<\/h3>\n<p>Participant flow is shown in Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0001\">1<\/a>.<\/p>\n<section class=\"article-section__inline-figure\">\n<figure id=\"sct312883-fig-0001\" class=\"figure\"><a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/d4dee8e7-acfa-465a-b0ab-a37aee6567d0\/sct312883-fig-0001-m.jpg\" target=\"_blank\" rel=\"noopener noreferrer\"> <picture><source srcset=\"\/cms\/asset\/d4dee8e7-acfa-465a-b0ab-a37aee6567d0\/sct312883-fig-0001-m.jpg\" media=\"(min-width: 1650px)\" \/><img decoding=\"async\" class=\"figure__image\" title=\"image\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/3f3ed63f-2c0f-4fcb-af75-28dce37a0e31\/sct312883-fig-0001-m.png\" alt=\"image\" data-lg-src=\"\/cms\/asset\/d4dee8e7-acfa-465a-b0ab-a37aee6567d0\/sct312883-fig-0001-m.jpg\" \/><\/picture><\/a><figcaption class=\"figure__caption\">\n<div class=\"figure__caption__header\"><strong class=\"figure__title\">FIGURE 1<\/strong><\/p>\n<div class=\"figure-extra\"><a class=\"open-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\">Open in figure viewer<\/a><a class=\"ppt-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/downloadFigures?id=sct312883-fig-0001&amp;doi=10.1002%2Fsctm.20-0472\"><i class=\"icon-Icon_Download\"><\/i>PowerPoint<\/a><\/div>\n<\/div>\n<div class=\"figure__caption figure__caption-text\">Enrollment and randomization. UC\u2010MSC, umbilical cord mesenchymal stem cell<\/div>\n<\/figcaption><\/figure>\n<\/section>\n<\/section>\n<section id=\"sct312883-sec-0023\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0023-title\" class=\"article-section__sub-title section2\">3.2 Recruitment<\/h3>\n<p>From 25 April 2020, to 21 July 2020, a total of 28 subjects were enrolled. Four subjects were subsequently determined to be ineligible because of screen failure. Twenty\u2010four subjects were randomized (Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0001\">1<\/a>). At enrollment, 11 subjects (46%) were receiving invasive mechanical ventilation, and 13 (54%) were on high flow oxygen therapy via noninvasive ventilation (including high flow nasal cannula, continuous positive airways pressure, or bilevel positive airways pressure) prior to initiation of treatment.<\/p>\n<p>Demographics and baseline characteristics for enrolled subjects, along with stratification, randomization, and concomitant treatment information are presented in Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0001\">1<\/a> and Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a>.<\/p>\n<div id=\"sct312883-tbl-0001\" class=\"article-table-content\">\n<header class=\"article-table-caption\"><span class=\"table-caption__label\">TABLE 1. <\/span>Baseline characteristics and concomitant treatments during index of hospitalization by treatment group<\/header>\n<div class=\"article-table-content-wrapper\">\n<table class=\"table article-section__table\">\n<thead>\n<tr>\n<th class=\"bottom-bordered-cell right-bordered-cell left-aligned\">Characteristics and treatments<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">UC\u2010MSC (n = 12)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">Control (n = 12)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\"><i>P<\/i> value<\/th>\n<\/tr>\n<\/thead>\n<tbody>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Sex, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\">.41<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Male<\/td>\n<td class=\"left-aligned\">5 (41.7)<\/td>\n<td class=\"left-aligned\">8 (66.7)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Female<\/td>\n<td class=\"left-aligned\">7 (58.3)<\/td>\n<td class=\"left-aligned\">4 (33.3)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Age, mean\u2009\u00b1\u2009SD, years<\/td>\n<td class=\"left-aligned\">58.58\u2009\u00b1\u200915.93<\/td>\n<td class=\"left-aligned\">58.83\u2009\u00b1\u200911.61<\/td>\n<td class=\"center-aligned\">.97<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Race, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">White<\/td>\n<td class=\"left-aligned\">11 (91.7)<\/td>\n<td class=\"left-aligned\">10 (83.3)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">African American<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"left-aligned\">2 (16.7)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Ethnicity, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Hispanic or Latino<\/td>\n<td class=\"left-aligned\">11 (91.7)<\/td>\n<td class=\"left-aligned\">11 (91.7)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Non\u2010Hispanic<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">PaO<sub>2<\/sub>\/FiO<sub>2<\/sub> ratio at enrollment, median (IQR)<\/td>\n<td class=\"left-aligned\">124 (68\u2010164)<\/td>\n<td class=\"left-aligned\">108.5 (68.5\u2010165.5)<\/td>\n<td class=\"center-aligned\">.67<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">ARDS severity stratification, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Mild\u2010to\u2010moderate<\/td>\n<td class=\"left-aligned\">3 (25)<\/td>\n<td class=\"left-aligned\">3 (25)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Moderate\u2010to\u2010severe<\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">BMI, mean\u2009\u00b1\u2009SD, kg\/m<sup>2<\/sup><\/td>\n<td class=\"left-aligned\">34.5\u2009\u00b1\u20094.5<\/td>\n<td class=\"left-aligned\">29.6\u2009\u00b1\u20093.5<\/td>\n<td class=\"center-aligned\">.01<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Smoker (former), n (%)<\/td>\n<td class=\"left-aligned\">0<\/td>\n<td class=\"left-aligned\">2 (16.7)<\/td>\n<td class=\"center-aligned\">.48<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Comorbidities, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Diabetes<\/td>\n<td class=\"left-aligned\">5 (41.7)<\/td>\n<td class=\"left-aligned\">6 (50)<\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Hypertension<\/td>\n<td class=\"left-aligned\">7 (58.3)<\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"center-aligned\">.67<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Obesity (BMI &gt;30)<\/td>\n<td class=\"left-aligned\">11 (91.7)<\/td>\n<td class=\"left-aligned\">5 (41.7)<\/td>\n<td class=\"center-aligned\">.03<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Cancer<\/td>\n<td class=\"left-aligned\">0<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Heart disease<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"left-aligned\">3 (25)<\/td>\n<td class=\"center-aligned\">.59<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Concomitant treatments, n (%)<\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"center-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Heparin<\/td>\n<td class=\"left-aligned\">12 (100)<\/td>\n<td class=\"left-aligned\">12 (100)<\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Only prophylactic dose heparin<a id=\"sct312883-note-0003_31-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0003_31\"><sup>a<\/sup><\/a><\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"left-aligned\">7 (58.3)<\/td>\n<td class=\"center-aligned\">.67<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Therapeutic dose heparin<a id=\"sct312883-note-0004_32-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0004_32\"><sup>b<\/sup><\/a><\/td>\n<td class=\"left-aligned\">3 (25)<\/td>\n<td class=\"left-aligned\">5 (41.7)<\/td>\n<td class=\"center-aligned\">.67<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Remdesivir<\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"left-aligned\">7 (58.3)<\/td>\n<td class=\"center-aligned\">.67<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Convalescent plasma<\/td>\n<td class=\"left-aligned\">3 (25)<\/td>\n<td class=\"left-aligned\">4 (33.3)<\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Corticosteroids<\/td>\n<td class=\"left-aligned\">10 (83.3)<\/td>\n<td class=\"left-aligned\">9 (75)<\/td>\n<td class=\"center-aligned\">0.99<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Tocilizumab<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"left-aligned\">4 (33.3)<\/td>\n<td class=\"center-aligned\">.32<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Hydroxychloroquine<\/td>\n<td class=\"left-aligned\">1 (8.3)<\/td>\n<td class=\"left-aligned\">2 (18.2)<\/td>\n<td class=\"center-aligned\">.59<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Alteplase<\/td>\n<td class=\"left-aligned\">0<\/td>\n<td class=\"left-aligned\">2 (16.7)<\/td>\n<td class=\"center-aligned\">.48<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<div class=\"article-section__table-footnotes\">\n<ul>\n<li id=\"sct312883-note-0001\"><i>Note:<\/i> Age and BMI are normally distributed. PaO<sub>2<\/sub>\/FiO<sub>2<\/sub> ratio at enrollment is non\u2010normally distributed. <i>t<\/i> test, Wilcoxon two\u2010sample test, and Fisher&#8217;s exact test were used for continuous normal, continuous non\u2010normal and categorical variables, respectively.<\/li>\n<li id=\"sct312883-note-0002\">Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass index; FiO<sub>2<\/sub>, fraction of inspired oxygen; IQR, interquartile range; PaO<sub>2<\/sub>, partial pressure of oxygen; UC\u2010MSC, umbilical cord mesenchymal stem cell.<\/li>\n<li id=\"sct312883-note-0003\" title=\"Footnote 1\"><span class=\"number\"><sup>a<\/sup> <\/span> Prophylactic dose heparin: either prophylactic unfractionated heparin, subcutaneous injection, 5000\u2009units two to three times daily (up to 15\u2009000\u2009units) or prophylactic enoxaparin 40 to 60\u2009mg daily.<\/li>\n<li id=\"sct312883-note-0004\" title=\"Footnote 2\"><span class=\"number\"><sup>b<\/sup> <\/span> Therapeutic dose heparin: either full dose unfractionated heparin, intravenous, titrated to a goal of activated partial thromboplastin time, or full dose enoxaparin 1 mg\/kg twice daily.<\/li>\n<\/ul>\n<\/div>\n<div class=\"article-section__table-source\"><\/div>\n<\/div>\n<p>Two cases required special considerations. Subject #11 died for reasons unrelated to COVID\u201019 after failed endotracheal intubation. Therefore, this subject was considered as censored in the data analysis for time to COVID\u201019\u2010related death and time to recovery outcomes. Subject #24 left the hospital against medical advice 11\u2009days after second infusion and was thus considered as censored in the time to recovery analysis. This patient eventually recovered at home and was confirmed alive at 31\u2009days after the first infusion.<\/p>\n<p>A Data Safety Monitoring Board reviewed all safety data.<\/p>\n<p>At the time of this writing, all subjects have been followed for 31\u2009days after the first infusion, corresponding to 28\u2009days after the second infusion.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0024\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0024-title\" class=\"article-section__sub-title section2\">3.3 Baseline data<\/h3>\n<p>Twelve subjects were randomized to the UC\u2010MSC treatment group (age 59\u2009\u00b1\u200916\u2009years; 7 women [58%]) and 12 to the control group (age 59\u2009\u00b1\u200912\u2009years; 4 women [33%]) (Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0001\">1<\/a>; Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a>). The age of enrolled subjects was 59\u2009\u00b1\u200914\u2009years (mean\u2009\u00b1\u2009SD).<\/p>\n<p>Three subjects in each group were stratified to the mild\u2010to\u2010moderate ARDS severity stratum, and nine subjects in each group into the moderate\u2010to\u2010severe stratum. There were no significant differences in concomitant treatments between the groups (Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0001\">1<\/a>; Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a>). The only differences observed in baseline characteristics and comorbidities were in body mass index and obesity, which were higher in the UC\u2010MSC treatment group (Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0001\">1<\/a>; Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a>). The analysis was by original assigned groups.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0025\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0025-title\" class=\"article-section__sub-title section2\">3.4 Investigational product<\/h3>\n<p>An average of 98.7 \u00d7\u200910<sup>6<\/sup> UC\u2010MSCs were administered per infusion. The viability of UC\u2010MSCs (investigational product) at the time of product release for administration was found to be 96.2%\u2009\u00b1\u20091.8% by trypan blue and 88.4%\u2009\u00b1\u20097.6% by flow cytometry using fixable viability stain. Apoptosis, assessed by activated caspase\u20103, was found to be 2.4%\u2009\u00b1\u20093.7%, by flow cytometry (Figure <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S1<\/a>). No differences in cell dose, cell viability, or degree of apoptosis were observed between UC\u2010MSCs (investigational product) prepared for the first or second infusion. Stability studies demonstrated stability of the UC\u2010MSC investigational product for up to 8 hours after thawing and preparation, as assessed by cell count, viability by trypan blue and flow cytometry, and apoptosis assessed by flow cytometry. Cell surface marker analysis demonstrated a typical surface marker profile characteristic of MSCs: CD90 of 97.9%\u2009\u00b1\u20092.6%, CD105 of 98.1%\u2009\u00b1\u20091.4%, and CD34\/CD45 of 2.2%\u2009\u00b1\u20094.9% (Figure <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S1<\/a>).<\/p>\n<\/section>\n<section id=\"sct312883-sec-0026\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0026-title\" class=\"article-section__sub-title section2\">3.5 Outcomes and estimations<\/h3>\n<p>A total of nine deaths were documented by day 28 after the second infusion. Two deaths occurred in the UC\u2010MSC treatment group and seven deaths in the control group. One subject (Subject #11) in the UC\u2010MSC treatment group died as a result of a failed endotracheal intubation. This outcome was deemed to be unrelated to the patient&#8217;s COVID\u201019 disease. Therefore, data analyses for this subject were censored at the time of failed endotracheal intubation.<\/p>\n<p>The details of all deaths are presented in Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S3<\/a>.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0027\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0027-title\" class=\"article-section__sub-title section2\">3.6 Adverse events<\/h3>\n<p>Two serious adverse events (SAEs) were observed in the UC\u2010MSC group and 16 SAEs in the control group, affecting 2 of 12 and 8 of 12 subjects, respectively (<i>P<\/i> =\u2009.04; Fisher&#8217;s exact test). There were significantly more subjects experiencing SAEs in the control group than in the UC\u2010MSC treatment group. The adverse events in all subjects are summarized in Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0002\">2<\/a>.<\/p>\n<div id=\"sct312883-tbl-0002\" class=\"article-table-content\">\n<header class=\"article-table-caption\"><span class=\"table-caption__label\">TABLE 2. <\/span>Summary of all adverse events for randomized subjects<\/header>\n<div class=\"article-table-content-wrapper\">\n<table class=\"table article-section__table\">\n<thead>\n<tr>\n<th class=\"bottom-bordered-cell right-bordered-cell left-aligned\">Topics<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">UC\u2010MSC treatment, n (%)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">Controls, n (%)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">Total (n = 24; 12 per group), n (%)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">Fisher&#8217;s exact test<\/th>\n<\/tr>\n<\/thead>\n<tbody>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of AEs reported<\/td>\n<td class=\"left-aligned\">35<\/td>\n<td class=\"left-aligned\">53<\/td>\n<td class=\"left-aligned\">88<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of subjects with AEs<a id=\"sct312883-note-0006_43-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0006_43\"><sup>a<\/sup><\/a><\/td>\n<td class=\"left-aligned\">8<\/td>\n<td class=\"left-aligned\">11<\/td>\n<td class=\"left-aligned\">19<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of SAEs reported<\/td>\n<td class=\"left-aligned\">2<\/td>\n<td class=\"left-aligned\">16<\/td>\n<td class=\"left-aligned\">18<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of subjects with SAEs<a id=\"sct312883-note-0006_44-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0006_44\"><sup>a<\/sup><\/a><\/td>\n<td class=\"left-aligned\">2<\/td>\n<td class=\"left-aligned\">8<\/td>\n<td class=\"left-aligned\">10<\/td>\n<td class=\"left-aligned\"><i>P<\/i> =\u2009.04<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of AEs by severity<a id=\"sct312883-note-0007_45-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0007_45\"><sup>b<\/sup><\/a><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Mild<\/td>\n<td class=\"left-aligned\">13 (37)<\/td>\n<td class=\"left-aligned\">13 (24)<\/td>\n<td class=\"left-aligned\">26 (30)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Moderate<\/td>\n<td class=\"left-aligned\">18 (51)<\/td>\n<td class=\"left-aligned\">21 (40)<\/td>\n<td class=\"left-aligned\">39 (44)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Severe<\/td>\n<td class=\"left-aligned\">4 (12)<\/td>\n<td class=\"left-aligned\">19 (36)<\/td>\n<td class=\"left-aligned\">23 (26)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Subjects with AEs by severity<a id=\"sct312883-note-0008_46-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0008_46\"><sup>c<\/sup><\/a><sup>,<\/sup><a id=\"sct312883-note-0009_47-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0009_47\"><sup>d<\/sup><\/a><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Mild<\/td>\n<td class=\"left-aligned\">7 (44)<\/td>\n<td class=\"left-aligned\">5 (25)<\/td>\n<td class=\"left-aligned\">12 (33)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Moderate<\/td>\n<td class=\"left-aligned\">7 (44)<\/td>\n<td class=\"left-aligned\">8 (40)<\/td>\n<td class=\"left-aligned\">15 (42)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Severe<\/td>\n<td class=\"left-aligned\">2 (12)<\/td>\n<td class=\"left-aligned\">7 (35)<\/td>\n<td class=\"left-aligned\">9 (25)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Number of AEs by relatedness to treatment<a id=\"sct312883-note-0007_48-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0007_48\"><sup>b<\/sup><\/a><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Unrelated<\/td>\n<td class=\"left-aligned\">31 (89)<\/td>\n<td class=\"left-aligned\">45 (85)<\/td>\n<td class=\"left-aligned\">76 (86)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Unlikely<\/td>\n<td class=\"left-aligned\">3 (9)<\/td>\n<td class=\"left-aligned\">7 (13)<\/td>\n<td class=\"left-aligned\">10 (11)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Possible<\/td>\n<td class=\"left-aligned\">1 (3)<\/td>\n<td class=\"left-aligned\">1 (2)<\/td>\n<td class=\"left-aligned\">2 (3)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Probable<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Definite<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\">0 (0)<\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Subjects with AEs by relatedness to treatment<a id=\"sct312883-note-0008_49-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0008_49\"><sup>c<\/sup><\/a><sup>,<\/sup><a id=\"sct312883-note-0009_50-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0009_50\"><sup>d<\/sup><\/a><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<td class=\"left-aligned\"><\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Unrelated<\/td>\n<td class=\"left-aligned\">8 (80)<\/td>\n<td class=\"left-aligned\">10 (67)<\/td>\n<td class=\"left-aligned\">18 (72)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Unlikely<\/td>\n<td class=\"left-aligned\">1 (10)<\/td>\n<td class=\"left-aligned\">4 (26)<\/td>\n<td class=\"left-aligned\">5 (20)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Possible<\/td>\n<td class=\"left-aligned\">1 (10)<\/td>\n<td class=\"left-aligned\">1 (7)<\/td>\n<td class=\"left-aligned\">2 (8)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Probable<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">Definite<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">0 (0.0)<\/td>\n<td class=\"left-aligned\">NS<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<div class=\"article-section__table-footnotes\">\n<ul>\n<li id=\"sct312883-note-0005\">Abbreviations: AE, adverse event; SAE, serious adverse event; NS, not significant; UC\u2010MSC, umbilical cord mesenchymal stem cell.<\/li>\n<li id=\"sct312883-note-0006\" title=\"Footnote 1\"><span class=\"number\"><sup>a<\/sup> <\/span> Subjects who experience one or more AEs or SAEs are counted only once.<\/li>\n<li id=\"sct312883-note-0007\" title=\"Footnote 2\"><span class=\"number\"><sup>b<\/sup> <\/span> Percentages are based on number of AEs reported for each treatment group.<\/li>\n<li id=\"sct312883-note-0008\" title=\"Footnote 3\"><span class=\"number\"><sup>c<\/sup> <\/span> Subjects are counted only once within a particular severity grade or relatedness category.<\/li>\n<li id=\"sct312883-note-0009\" title=\"Footnote 4\"><span class=\"number\"><sup>d<\/sup> <\/span> Percentages are based on n for each treatment group.<\/li>\n<\/ul>\n<\/div>\n<div class=\"article-section__table-source\"><\/div>\n<\/div>\n<\/section>\n<section id=\"sct312883-sec-0028\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0028-title\" class=\"article-section__sub-title section2\">3.7 Primary endpoint<\/h3>\n<p>The primary endpoint was safety, defined as the occurrence of prespecified infusion\u2010associated AEs within 6 hours after infusion in addition to cardiac arrest or death within 24\u2009hours after infusion. Prespecified infusion\u2010associated AEs are outlined in Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0003\">3<\/a>. One subject in each group developed infusion\u2010associated AEs. UC\u2010MSC treatment was found to be safe, as it did not lead to an increase in prespecified infusion\u2010associated AEs. In the UC\u2010MSC treatment group, the only reported adverse event occurred in a subject with bradycardia, who experienced worsening of bradycardia and required transient vasopressor treatment. In the control group, all prespecified infusion\u2010associated AEs occurred in the same subject, who experienced cardiac arrest 2 hours after infusion of vehicle solution. In each group, one subject developed infusion\u2010associated AEs.<\/p>\n<div id=\"sct312883-tbl-0003\" class=\"article-table-content\">\n<header class=\"article-table-caption\"><span class=\"table-caption__label\">TABLE 3. <\/span>Primary endpoint: Safety<\/header>\n<div class=\"article-table-content-wrapper\">\n<table class=\"table article-section__table\">\n<thead>\n<tr>\n<th class=\"bottom-bordered-cell right-bordered-cell left-aligned\" rowspan=\"2\">Adverse event<\/th>\n<th class=\"bottom-bordered-cell left-aligned\" colspan=\"2\">Adverse events<\/th>\n<\/tr>\n<tr>\n<th class=\"bottom-bordered-cell left-aligned\">UC\u2010MSC treatment (n = 12), n (%)<\/th>\n<th class=\"bottom-bordered-cell left-aligned\">Control (n = 12), n (%)<\/th>\n<\/tr>\n<\/thead>\n<tbody>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1a. An increase in vasopressor dose<\/td>\n<td class=\"center-aligned\">1<a id=\"sct312883-note-0011_52-controller\" class=\"noteLink scrollableLink\" title=\"Link to note\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-note-0011_52\"><sup>a<\/sup><\/a><\/td>\n<td class=\"center-aligned\">1<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1b. In patients receiving mechanical ventilation: worsening hypoxemia<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">0<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1c. In patients receiving high flow oxygen therapy: worsening hypoxemia, as indicated by requirement of intubation and mechanical ventilation<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">0<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1d. New cardiac arrhythmia requiring cardioversion<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">1<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1e. New ventricular tachycardia, ventricular fibrillation, or asystole<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">1<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">1f. A clinical scenario consistent with transfusion incompatibility or transfusion\u2010related infection<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">0<\/td>\n<\/tr>\n<tr>\n<td class=\"right-bordered-cell left-aligned\">2. Cardiac arrest or death within 24\u2009h postinfusion<\/td>\n<td class=\"center-aligned\">0<\/td>\n<td class=\"center-aligned\">0<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<div class=\"article-section__table-footnotes\">\n<ul>\n<li id=\"sct312883-note-0010\"><i>Note:<\/i> Safety: as defined by the occurrence of prespecified infusion\u2010associated adverse events within 6 hours (1a\u20101f) and occurrence of cardiac arrest or death within 24\u2009hours postinfusion (2).<\/li>\n<li id=\"sct312883-note-0011\" title=\"Footnote 1\"><span class=\"number\"><sup>a<\/sup> <\/span> The vasopressor dose increase was ordered by the primary treating physician before the infusion started, but it was not given until hours later, after the infusion.<\/li>\n<\/ul>\n<\/div>\n<div class=\"article-section__table-source\"><\/div>\n<\/div>\n<\/section>\n<section id=\"sct312883-sec-0029\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0029-title\" class=\"article-section__sub-title section2\">3.8 Secondary endpoints<\/h3>\n<p>At 31\u2009days after the first infusion (corresponding to 28\u2009days after the last infusion), patient survival was significantly improved in the UC\u2010MSC vs the control group: 10 of 11 (91%) vs 5 of 12 (42%), respectively (<i>P<\/i> =\u2009.015). The hazard ratio for death comparing the control group with UC\u2010MSC treatment group was 8.76 (95% confidence interval [CI]: 1.07\u201071.4), indicating that the control group had a higher risk of death. Kaplan\u2010Meier estimates are presented in Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0002\">2A<\/a> (survival).<\/p>\n<section class=\"article-section__inline-figure\">\n<figure id=\"sct312883-fig-0002\" class=\"figure\"><a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/e9744ca3-e69d-499a-a0ef-82d26e1c09f9\/sct312883-fig-0002-m.jpg\" target=\"_blank\" rel=\"noopener noreferrer\"> <picture><source srcset=\"\/cms\/asset\/e9744ca3-e69d-499a-a0ef-82d26e1c09f9\/sct312883-fig-0002-m.jpg\" media=\"(min-width: 1650px)\" \/><img decoding=\"async\" class=\"figure__image\" title=\"image\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/80623278-e66b-4e91-b181-aa6f61adaa76\/sct312883-fig-0002-m.png\" alt=\"image\" data-lg-src=\"\/cms\/asset\/e9744ca3-e69d-499a-a0ef-82d26e1c09f9\/sct312883-fig-0002-m.jpg\" \/><\/picture><\/a><figcaption class=\"figure__caption\">\n<div class=\"figure__caption__header\"><strong class=\"figure__title\">FIGURE 2<\/strong><\/p>\n<div class=\"figure-extra\"><a class=\"open-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\">Open in figure viewer<\/a><a class=\"ppt-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/downloadFigures?id=sct312883-fig-0002&amp;doi=10.1002%2Fsctm.20-0472\"><i class=\"icon-Icon_Download\"><\/i>PowerPoint<\/a><\/div>\n<\/div>\n<div class=\"figure__caption figure__caption-text\">Kaplan\u2010Meier curves. A, Survival. At 31\u2009days after the first infusion (corresponding to 28\u2009days after the last infusion), patient survival was 91% vs 42% in the UC\u2010MSC and control group, respectively (<i>P<\/i> =\u2009.015). The difference between the groups was statistically significant. B, SAE\u2010free survival. SAE\u2010free survival was significantly improved in the UC\u2010MSC treatment group compared with the control group (<i>P<\/i> =\u2009.008). SAEs affected two vs eight patients in the UC\u2010MSC and control group, respectively. C, Time to recovery. Time to recovery was significantly shorter in the UC\u2010MSC treatment group compared with the control group (<i>P<\/i> =\u2009.031). Censoring was limited to dropout from study, and the event of interest was recovery. In the case of death, the patient&#8217;s time to recovery was considered censored at the end of study observation; thus the patient conservatively remained in the risk set for all Kaplan\u2010Meier estimation throughout the study period. CI, confidence interval; HR, hazard ratio; SAE, serious adverse event; UC\u2010MSC, umbilical cord mesenchymal stem cell<\/div>\n<\/figcaption><\/figure>\n<\/section>\n<p>SAE\u2010free survival was significantly improved in the UC\u2010MSC treatment group (<i>P<\/i> =\u2009.0081). The hazard ratio for SAE, comparing the control group with the UC\u2010MSC treatment group, was 6.22 (95% CI: 1.33\u201028.96), indicating that the control group experienced an increased risk of SAEs. Kaplan\u2010Meier estimates are presented in Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0002\">2B<\/a> (SAE\u2010free survival).<\/p>\n<p>Time to recovery was significantly shorter in the UC\u2010MSC treatment group (<i>P<\/i> =\u2009.0307). The hazard ratio for recovery comparing the control group with the UC\u2010MSC treatment group was 0.29 (95% CI: 0.09\u20100.95); this is evidence of a lower rate of recovery for the control group. Kaplan\u2010Meier estimates are presented in Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0002\">2C<\/a> (time to recovery).<\/p>\n<\/section>\n<section id=\"sct312883-sec-0030\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0030-title\" class=\"article-section__sub-title section2\">3.9 Analysis of viral load in peripheral blood plasma<\/h3>\n<p>The median viral load at day 0 or day 6 did not differ significantly between the UC\u2010MSC treatment and control group. The <i>P<\/i> values were .196 and .136 for day 0 and day 6, respectively (Figure <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a>).<\/p>\n<\/section>\n<section id=\"sct312883-sec-0031\" class=\"article-section__sub-content\">\n<h3 id=\"sct312883-sec-0031-title\" class=\"article-section__sub-title section2\">3.10 Analysis of inflammatory cytokines and chemokines levels in peripheral blood plasma<\/h3>\n<p>The blood plasma levels of 10 inflammation\u2010related proteins were assessed by quantitative enzyme\u2010linked immunosorbent assay in both UC\u2010MSC treatment and control groups on days 0 and 6. Baseline levels of proteins tested were comparable in both UC\u2010MSC and control groups (Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0003\">3<\/a>; day 0 column, unpaired <i>t<\/i> tests), with the exception of IL\u20106, which showed higher baseline levels in the control group (<i>P<\/i> &lt;\u2009.05, an imbalance between groups possibly resulting from the small sample size). At 6\u2009days after treatment initiation, we observed significant differences between the groups, and a consistent decrease in inflammatory markers only in the UC\u2010MSC treatment group. In a comparison between groups at day 6, we observed significant differences in the concentration of GM\u2010CSF, IFNg, IL\u20105, IL\u20106, IL\u20107, TNFa, TNFb, PDGF\u2010BB, and RANTES (<i>P<\/i> &lt;\u2009.05); median values of these molecules were lower in the UC\u2010MSC group (Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0003\">3<\/a>; day 6 column, unpaired <i>t<\/i> tests). The difference in IL\u20102 resulted very close to statistical significance (<i>P<\/i> =\u2009.051) (Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0003\">3<\/a>; day 6 column, IL\u20102). In the longitudinal analysis, inflammatory cytokine concentrations showed marked and statistically significant decreases from day 0 to day 6 only in the UC\u2010MSC treatment group (Figure <a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-fig-0003\">3<\/a>; UC\u2010MSC treatment and control columns, paired <i>t<\/i> tests).<\/p>\n<section class=\"article-section__inline-figure\">\n<figure id=\"sct312883-fig-0003\" class=\"figure\"><a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/98b8a81e-54ee-45f9-92f4-f9a7a5abf225\/sct312883-fig-0003-m.jpg\" target=\"_blank\" rel=\"noopener noreferrer\"> <picture><source srcset=\"\/cms\/asset\/98b8a81e-54ee-45f9-92f4-f9a7a5abf225\/sct312883-fig-0003-m.jpg\" media=\"(min-width: 1650px)\" \/><img decoding=\"async\" class=\"figure__image\" title=\"image\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/e677b5d7-7109-45da-93e1-f0e14e3d5358\/sct312883-fig-0003-m.png\" alt=\"image\" data-lg-src=\"\/cms\/asset\/98b8a81e-54ee-45f9-92f4-f9a7a5abf225\/sct312883-fig-0003-m.jpg\" \/><\/picture><\/a><figcaption class=\"figure__caption\">\n<div class=\"figure__caption__header\"><strong class=\"figure__title\">FIGURE 3<\/strong><\/p>\n<div class=\"figure-extra\"><a class=\"open-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\">Open in figure viewer<\/a><a class=\"ppt-figure-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/downloadFigures?id=sct312883-fig-0003&amp;doi=10.1002%2Fsctm.20-0472\"><i class=\"icon-Icon_Download\"><\/i>PowerPoint<\/a><\/div>\n<\/div>\n<div class=\"figure__caption figure__caption-text\">Analysis of inflammatory cytokines, chemokines, and growth factors in plasma of randomized subjects. In the comparison between groups at day 6 and in the longitudinal analysis from day 0 to day 6, inflammatory cytokine concentrations showed marked and statistically significant decreases from day 0 to day 6 only in the UC\u2010MSC treatment group. The overall \u201csignature\u201d of the response in the UC\u2010MSC treatment group is characterized by a reduction of the levels of key inflammatory molecules involved in the COVID\u201019 \u201ccytokine storm,\u201d including IFNg, IL\u20106, and TNFa cytokines and RANTES chemokine. GM\u2010CSF and PDGF\u2010BB also decreased significantly only in the UC\u2010MSC treatment group. ns, not significant; UC\u2010MSC, umbilical cord mesenchymal stem cell<\/div>\n<\/figcaption><\/figure>\n<\/section>\n<\/section>\n<\/section>\n<section id=\"sct312883-sec-0032\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0032-title\" class=\"article-section__title section__title section1\">4 DISCUSSION<\/h2>\n<p>Severe COVID\u201019 is believed to result from a hyperinflammatory state and overactive immune response with cytokine storm and immunothrombosis elicited by SARS\u2010CoV\u20102 infection.<sup><a id=\"sct312883-bib-0005R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0005\" data-tab=\"pane-pcw-references\">5<\/a>, <a id=\"sct312883-bib-0040R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0040\" data-tab=\"pane-pcw-references\">40<\/a>, <a id=\"sct312883-bib-0041R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0041\" data-tab=\"pane-pcw-references\">41<\/a><\/sup> Patients with severe COVID\u201019 frequently develop ARDS, which is associated with poor prognosis.<sup><a id=\"sct312883-bib-0004R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0004\" data-tab=\"pane-pcw-references\">4<\/a>, <a id=\"sct312883-bib-0040R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0040\" data-tab=\"pane-pcw-references\">40<\/a><\/sup> Mortality in COVID\u201019 is associated with ARDS and multiple organ failure.<sup><a id=\"sct312883-bib-0042R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0042\" data-tab=\"pane-pcw-references\">42<\/a><\/sup> Mortality in patients with COVID\u201019 and ARDS was reported to be 52.4%.<sup><a id=\"sct312883-bib-0010R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0010\" data-tab=\"pane-pcw-references\">10<\/a><\/sup> Various treatment modalities have been investigated and recently reported, including dexamethasone<sup><a id=\"sct312883-bib-0011R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0011\" data-tab=\"pane-pcw-references\">11<\/a><\/sup> and convalescent plasma.<sup><a id=\"sct312883-bib-0043R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0043\" data-tab=\"pane-pcw-references\">43<\/a><\/sup> Yet, there remains a need for therapies that can modulate the inflammatory response, shorten the course of disease, and further improve survival.<\/p>\n<p>UC\u2010MSCs may have beneficial effects in patients with severe COVID\u201019 by modulating immune responses and altering the immunopathogenic cytokine storm.<sup><a id=\"sct312883-bib-0030R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0030\" data-tab=\"pane-pcw-references\">30<\/a>&#8211;<a id=\"sct312883-bib-0032R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0032\" data-tab=\"pane-pcw-references\">32<\/a><\/sup> The cells used in this trial were derived from the subepithelial lining of the umbilical cord and can be rapidly expanded for clinical applications under strict Good Manufacturing Practice conditions.<sup><a id=\"sct312883-bib-0037R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0037\" data-tab=\"pane-pcw-references\">37<\/a><\/sup> UC\u2010MSCs were reported to be safe in clinical trials in other disease states and have been safely administered across histocompatibility barriers.<sup><a id=\"sct312883-bib-0044R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0044\" data-tab=\"pane-pcw-references\">44<\/a>&#8211;<a id=\"sct312883-bib-0046R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0046\" data-tab=\"pane-pcw-references\">46<\/a><\/sup> Because of their immunomodulatory functions, UC\u2010MSCs have already been tested in the treatment of autoimmune and inflammatory disorders. Clinical applications using UC\u2010MSCs processed at our cGMP facility have been authorized by the FDA in subjects with T1D (IND#018302) and Alzheimer&#8217;s disease (IND#18200).<\/p>\n<p>Several clinical trials have been conducted to test MSCs as treatment of ARDS, mainly focused on determining safety.<sup><a id=\"sct312883-bib-0025R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0025\" data-tab=\"pane-pcw-references\">25<\/a>&#8211;<a id=\"sct312883-bib-0029R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0029\" data-tab=\"pane-pcw-references\">29<\/a><\/sup> Variable results have been reported, possibly because of differences in trial design and quality of the cell product used. Improved outcomes were recently reported in patients with COVID\u201019 pneumonia treated with angiotensin converting enzyme \u2010 2 (ACE\u20102)\u2010negative MSCs.<sup><a id=\"sct312883-bib-0030R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0030\" data-tab=\"pane-pcw-references\">30<\/a><\/sup> Additional pilot studies of UC\u2010MSCs for COVID\u201019 also reported promising results.<sup><a id=\"sct312883-bib-0031R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0031\" data-tab=\"pane-pcw-references\">31<\/a>&#8211;<a id=\"sct312883-bib-0033R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0033\" data-tab=\"pane-pcw-references\">33<\/a><\/sup><\/p>\n<p>Based on previous encouraging results by other groups,<sup><a id=\"sct312883-bib-0030R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0030\" data-tab=\"pane-pcw-references\">30<\/a>&#8211;<a id=\"sct312883-bib-0033R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0033\" data-tab=\"pane-pcw-references\">33<\/a><\/sup> our experience with cell therapy clinical protocols, and the urgent need to develop effective therapeutic strategies, the purpose of this RCT was to determine safety and explore efficacy of UC\u2010MSCs for treatment of subjects with ARDS secondary to COVID\u201019 (<a class=\"linkBehavior\" href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/a> identifier: NCT04355728).<\/p>\n<p>The current report presents, for the first time, the results of a double\u2010blind, phase 1\/2a RCT testing UC\u2010MSCs in 24 subjects with COVID\u201019 and ARDS. There was overall balance in the distribution of baseline characteristics, comorbidities, or concomitant treatments between the groups. No serious adverse events related to UC\u2010MSC infusion were observed. There was no observed difference in number of subjects experiencing infusion\u2010associated adverse events. At 28\u2009days after the last infusion, patient survival was 91% in the UC\u2010MSC group and 42% in the control group (<i>P<\/i> =\u2009.015). Two SAEs were reported in the UC\u2010MSC group and 16 in the control group, affecting two and eight patients, respectively (<i>P<\/i> =\u2009.04). SAE\u2010free survival (<i>P<\/i> =\u2009.008) and time to recovery (<i>P<\/i> =\u2009.03) were significantly improved in the UC\u2010MSC treatment group.<\/p>\n<p>This study was not intended as an efficacy trial, but instead as an early phase study to establish safety. We relied on randomization to protect against imbalance in biasing preliminary estimates of efficacy. Stratified, blocked randomization was employed to evenly represent ARDS severity and changing standard of care over time between groups. Even with blocked randomization, confounding may exist because, with small numbers, there is still potential for imbalance. Table <a class=\"tableLink scrollableLink\" title=\"Link to table\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-tbl-0001\">1<\/a> and Table <a class=\"suppLink scrollableLink\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#support-information-section\">S2<\/a> illustrate overall balance in the distribution of demographic and clinical factors thought to be associated with COVID\u201019 trajectory. The only differences observed at baseline, in body mass index and obesity, would be expected to worsen COVID\u201019 outcomes in the UC\u2010MSC treatment group.<sup><a id=\"sct312883-bib-0047R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0047\" data-tab=\"pane-pcw-references\">47<\/a>, <a id=\"sct312883-bib-0048R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0048\" data-tab=\"pane-pcw-references\">48<\/a><\/sup> The viral load at baseline did not differ significantly between the UC\u2010MSC treatment and the control group. An important change in inclusion criteria is worthy of discussion. The study was initially designed to enroll patients receiving invasive mechanical ventilation. At the time of study inception, there were concerns regarding the potential for high flow oxygen therapy and noninvasive mechanical ventilation to increase aerosolization and infection risk in health care workers. Such concerns led practitioners to avoid these therapies and prompted infection control leadership to restrict them in our study sites. Subsequent studies called these concerns into question,<sup><a id=\"sct312883-bib-0049R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0049\" data-tab=\"pane-pcw-references\">49<\/a><\/sup> and high flow oxygen became broadly used. At that time, it appeared appropriate to include in our trial patients of similar disease severity but who were being treated with a different modality, and on 22 June 2020, we made a change in our inclusion criteria to reflect this. Subsequent studies have shown that high flow oxygen therapy is associated with a reduction in the proportion of patients who receive invasive mechanical ventilation, but no difference in mortality.<sup><a id=\"sct312883-bib-0012R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0012\" data-tab=\"pane-pcw-references\">12<\/a><\/sup> This supports the idea that the change of inclusion criteria did not necessarily alter the severity of patients enrolled but rather just reflects the secular trends and treatment patterns in the care of patients with a novel disease.<\/p>\n<p>The inferences we make from the efficacy results observed in this phase 1\/2a trial in 24 subjects, including the outcome of survival, are still subject to limitations of sample size and potential bias because of factors we were not yet aware of. However, results do provide preliminary evidence of a remarkable effect, which substantiates the need for further investigation in a larger, stratified, and adjusted clinical trial. In addition, based on our results and those from previously reported clinical trials, synergistic combination strategies could be explored, with agents that have shown a beneficial effect at similar stages of COVID\u201019 disease progression, such as dexamethasone<sup><a id=\"sct312883-bib-0011R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0011\" data-tab=\"pane-pcw-references\">11<\/a><\/sup> and convalescent plasma.<sup><a id=\"sct312883-bib-0043R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0043\" data-tab=\"pane-pcw-references\">43<\/a><\/sup><\/p>\n<p>The overall \u201csignature\u201d of the response in the UC\u2010MSC treatment group is characterized by a reduction of the levels of key inflammatory molecules involved in the COVID\u201019 \u201ccytokine storm,\u201d including IFNg, IL\u20106, and TNFa cytokines and RANTES chemokine.<sup><a id=\"sct312883-bib-0050R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0050\" data-tab=\"pane-pcw-references\">50<\/a><\/sup> In parallel, a reduction in GM\u2010CSF was observed. GM\u2010CSF is the main activator of the proinflammatory M1 macrophage phenotype; hence, its reduction could lead to macrophage polarization toward alternatively activated M2 macrophages.<sup><a id=\"sct312883-bib-0051R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0051\" data-tab=\"pane-pcw-references\">51<\/a><\/sup> The levels of PDGF\u2010BB also resulted significantly reduced in the UC\u2010MSC treatment group. Notably, PDGF\u2010BB stimulates mesenchymal cell activation, airway smooth muscle cell proliferation and migration, lung fibroblast cytokine production, and activation of nociceptive neurons.<sup><a id=\"sct312883-bib-0052R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0052\" data-tab=\"pane-pcw-references\">52<\/a>&#8211;<a id=\"sct312883-bib-0054R\" class=\"bibLink tab-link\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#sct312883-bib-0054\" data-tab=\"pane-pcw-references\">54<\/a><\/sup> Hence, it is possible that the administration of allogeneic MSCs could accelerate the steps of tissue repair in the lungs, decreasing the need for further mesenchymal cell activation.<\/p>\n<p>The positive response in subjects receiving UC\u2010MSC treatment seems to be more closely associated to a decrease in inflammatory cytokines, rather than a change in viral load.<\/p>\n<p>The observations made in this study could be of assistance for future studies in the field of COVID\u201019, ARDS, hyperinflammatory states, overactive immune responses, and autoimmunity. In addition, the preferential targeting of lung tissue after intravenous infusion could make UC\u2010MSCs particularly appealing for ARDS secondary to trauma, microbial infection, and pulmonary GvHD.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0033\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0033-title\" class=\"article-section__title section__title section1\">5 CONCLUSION<\/h2>\n<p>The results of this trial indicate that UC\u2010MSC infusions in COVID\u201019 with ARDS are safe. Moreover, UC\u2010MSC treatment was associated with a significant reduction in SAEs, mortality, and time to recovery, compared with controls.<\/p>\n<\/section>\n<div class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0034-title\" class=\"article-section__title section__title section1\"><span class=\"smallCaps\">ACKNOWLEDGMENTS<\/span><\/h2>\n<p>The authors wish to thank the North America&#8217;s Building Trades Unions (NABTU), The Cure Alliance, the Diabetes Research Institute Foundation (DRIF), the Barilla Group and Family, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, and Ugo Colombo for funding this clinical trial; Dr. Amit N Patel for the invaluable contributions to UC\u2010MSC manufacturing and infusion protocols over the years; Jadi Cell for providing the initial UC\u2010MSC master cell bank (cells provided at no cost by JadiCell \u2010 US Patent # 9,803,176 B2) used in this trial, further expanded at the Diabetes Research Institute (DRI) cGMP Facility to generate the Investigational Product; Drs. George Burke and Ronald Goldberg for serving as Medical Monitor and DSMB Chair; the DRI\u2010Cell Transplant Center cGMP Staff; Joana R.N. Lemos for the help with data analysis; Melissa Willman for the help in experimental design; and the Clinical Translational Research Site at the Miami Clinical and Translational Science Institute (UL1TR000460) from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. The trial was supported by unrestricted donations from the North America&#8217;s Building Trades Unions (NABTU), The Cure Alliance, the Diabetes Research Institute Foundation (DRIF), the Barilla Group and Family, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, and Ugo Colombo. This publication was supported by the Clinical Translational Research Site Grants Number UL1TR000460 and UL1TR002736 from the National Center for Advancing Translational Sciences (NCATS). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funding sources had no roles in study design, patient recruitment, data collection, data analysis, data interpretation, or writing the report. None of the authors has been paid to write this article by a pharmaceutical company or other agency. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit this manuscript for publication.<\/p>\n<\/div>\n<section id=\"sct312883-sec-0035\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0035-title\" class=\"article-section__title section__title section1\">CONFLICT OF INTEREST<\/h2>\n<p>The authors declared no potential conflicts of interest.<\/p>\n<\/section>\n<section id=\"sct312883-sec-0036\" class=\"article-section__content\">\n<h2 id=\"sct312883-sec-0036-title\" class=\"article-section__title section__title section1\"><span class=\"smallCaps\">AUTHOR CONTRIBUTIONS<\/span><\/h2>\n<p>G.L.: conception\/design, collection and\/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; E.L.: conception\/design, manuscript writing, final approval of manuscript, other (UC\u2010MSC manufacture); D.C.: collection and\/or assembly of data, manuscript writing, final approval of manuscript; S.M.C.: conception\/design, data analysis and interpretation, manuscript writing, final approval of manuscript; R.A.A.: conception\/design, manuscript writing, final approval of manuscript, other (implementation of the study); D.K.: collection and\/or assembly of data, manuscript writing, final approval of manuscript; A.A.G.: collection and\/or assembly of data, manuscript writing, final approval of manuscript, other (implementation of the study), other (clinical monitoring); R.P.: collection and\/or assembly of data, manuscript writing, final approval of manuscript, other (implementation of the study), other (clinical monitoring); P.R.: conception\/design, collection and\/or assembly of data, manuscript writing, final approval of manuscript; A.C.M.: manuscript writing, final approval of manuscript, other (implementation of the study); K.H.: manuscript writing, final approval of manuscript, other (protocol preparation), other (regulatory compliance and coordination); C.A.B.: collection and\/or assembly of data, manuscript writing, final approval of manuscript, other (implementation of the study); H.K.: collection and\/or assembly of data, manuscript writing, final approval of manuscript, other (implementation of the study); L. Rafkin: manuscript writing, final approval of manuscript, other (protocol preparation), other (regulatory compliance and coordination); D.B.: conception\/design, manuscript writing, final approval of manuscript, other (clinical monitoring); A.P. and K.G.: manuscript writing, final approval of manuscript, other (implementation of the study); C.L. and X.W.: manuscript writing, final approval of manuscript, other (UC\u2010MSC manufacture); A.M.A.M. and S.W.M.: data analysis and interpretation, manuscript writing, final approval of manuscript; L. Roque: manuscript writing, final approval of manuscript, other (protocol preparation), other (regulatory compliance and coordination); B.M.: manuscript writing, final approval of manuscript, other (regulatory compliance and coordination); N.S.K., E.G., X.X., J.T., A.I.C., and M.K.G.: conception\/design, manuscript writing, final approval of manuscript; R.A.: conception\/design, manuscript writing, final approval of manuscript, other (clinical monitoring); C.R.: conception\/design, manuscript writing, final approval of manuscript, other (principal investigator), other (clinical monitoring).<\/p>\n<\/section>\n<section id=\"openResearch\" class=\"article-section article-section__open-research\">\n<div class=\"accordion article-accordion\">\n<h2><a class=\"accordion__control\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/full\/10.1002\/sctm.20-0472?fbclid=IwAR3FR7I3I5NKaA-OYxpcRqfHy2UukiwhsKOAbGCyq4OqnhIwj_feF7O5ZQw#\"><span id=\"open-research-section\" class=\"section__title\">Open Research<\/span><i class=\"icon-section_arrow_d\"><\/i><\/a><\/h2>\n<\/div>\n<\/section>\n<section class=\"article-section article-section__supporting\">\n<div class=\"accordion article-accordion\">\n<div id=\"support-information-section\" class=\"section__title\" tabindex=\"0\">Supporting Information<i class=\"icon-section_arrow_d\"><\/i><\/div>\n<\/div>\n<\/section>\n<section id=\"references-section\" class=\"article-section article-section__references\">\n<div class=\"accordion article-accordion\">\n<div class=\"accordion__control\" tabindex=\"0\" data-references=\"\/action\/ajaxShowEnhancedAbstract?widgetId=5cf4c79f-0ae9-4dc5-96ce-77f62de7ada9&amp;ajax=true&amp;doi=10.1002%2Fsctm.20-0472&amp;pbContext=%3BrequestedJournal%3Ajournal%3A21576580%3Bpage%3Astring%3AArticle%2FChapter+View%3Bctype%3Astring%3AJournal+Content%3Bjournal%3Ajournal%3A21576580%3Bwgroup%3Astring%3APublication+Websites%3Bwebsite%3Awebsite%3Astemcellsjournals%3BpageGroup%3Astring%3APublication+Pages%3BsubPage%3Astring%3AFull+Text%3Barticle%3Aarticle%3Adoi%5C%3A10.1002%2Fsctm.20-0472%3Bcsubtype%3Astring%3AAhead+of+Print&amp;accordionHeadingWrapper=h2&amp;onlyLog=true\"><span id=\"references-section-1\" class=\"section__title\"><span class=\"smallCaps\">REFERENCES<\/span><\/span><i class=\"icon-section_arrow_d\"><\/i><\/div>\n<\/div>\n<\/section>\n<\/section>\n<\/article>\n<\/div>\n<\/div>\n<div class=\"col-lg-4 col-md-4 col-sm-4 hidden-xs hidden-sm hidden-md article-row-right fixed-element\">\n<div class=\"publication-cover-info clearfix\">\n<div class=\"cover-image-wrapper cover-image__image hasDetails\"><a title=\"View Early View articles\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/toc\/21576580\/0\/0\"><img decoding=\"async\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/cms\/asset\/f20a1533-c97b-4af8-abc2-5fe142a9e062\/sct3.v10.2.cover.jpg\" alt=\"\" \/><\/a><\/div>\n<div class=\"extra-info-wrapper cover-image__details\">\n<p class=\"cover-label\"><a title=\"View Early View articles\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/toc\/21576580\/0\/0\">Early View<\/a><\/p>\n<p class=\"cover-text\">Online Version of Record before inclusion in an issue<\/p>\n<div class=\"publication-cover-extra\"><label>This article also appears in:<\/label><\/p>\n<ul class=\"rlist\">\n<li><a href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/doi\/toc\/10.1002\/(ISSN)9999-0003.Covid-19-and-stem-cells\">COVID-19 and Stem Cells<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"clearfix mb-4\" data-widget-def=\"ux3-general-image\" data-widget-id=\"0355bc63-32e8-4623-a549-8ccca285472f\"><img decoding=\"async\" id=\"\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/pb-assets\/assets\/21576580\/SCTM_CoverIF_2019_v3-1593710247750.png\" alt=\"Impact factor 2019\" \/><\/div>\n<div class=\"pb-ad\">\n<div id=\"advert-rail-1\" class=\"advert advert-rail\" data-google-query-id=\"CNnJl4nT4u4CFTPBwgQdFd4NYg\">\n<div id=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_1__container__\"><iframe id=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_1\" title=\"3rd party ad content\" name=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_1\" width=\"300\" height=\"250\" frameborder=\"0\" marginwidth=\"0\" marginheight=\"0\" scrolling=\"no\" data-google-container-id=\"2\" data-load-complete=\"true\" data-mce-fragment=\"1\"><\/iframe><\/div>\n<\/div>\n<\/div>\n<div class=\"pb-ad\">\n<aside>\n<div id=\"advert-rail-2\" class=\"advert advert-rail\" data-google-query-id=\"CNrJl4nT4u4CFTPBwgQdFd4NYg\">\n<div id=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_2__container__\"><iframe id=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_2\" title=\"3rd party ad content\" name=\"google_ads_iframe_\/2215\/wly.cell.m.bio_000030\/stem-cells-transl-med_sct3_2\" width=\"300\" height=\"250\" frameborder=\"0\" marginwidth=\"0\" marginheight=\"0\" scrolling=\"no\" data-google-container-id=\"3\" data-load-complete=\"true\" data-mce-fragment=\"1\"><\/iframe><\/div>\n<\/div>\n<\/aside>\n<\/div>\n<div class=\"clearfix my-4\" data-widget-def=\"ux3-general-image\" data-widget-id=\"8a038e96-c28a-4604-b37e-996db14d0c1c\"><a title=\"Publish Your Negative Clinical Trial Results\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/hub\/journal\/21576580\/pages\/cfp-human-clinical-trials\" target=\"_blank\" rel=\"noopener noreferrer\"><img decoding=\"async\" id=\"\" src=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/pb-assets\/hub-assets\/stemcellsjournals\/HCA_Call4Papers-1584725735247.png\" alt=\"Publish Your Negative Clinical Trial Results\" \/><\/a><\/div>\n<div class=\"sticko__parent scrollThenFix\">\n<div class=\"tab tab--slide tab--flex sticko__md tabs--xs dynamic-sticko  tab--flex tabs--xs\">\n<ul class=\"rlist tab__nav w-slide--list cloned\" data-mobile-toggle=\"slide\">\n<li>\n<h2>Figures<\/h2>\n<\/li>\n<li>\n<h2>References<\/h2>\n<\/li>\n<li class=\"active\">\n<h2>Related<\/h2>\n<\/li>\n<li class=\"active\">\n<h2>Information<\/h2>\n<\/li>\n<\/ul>\n<ul class=\"rlist tab__content sticko__child\">\n<li id=\"pane-pcw-related\" class=\"tab__pane article-row-right__panes active empty\"><\/li>\n<li id=\"pane-pcw-details\" class=\"tab__pane article-row-right__panes active\">\n<section class=\"info-tab-wrapper\">\n<section class=\"metrics\">\n<h3 class=\"info-header\">Metrics<\/h3>\n<div class=\"section__body\">\n<div class=\"pb-dropzone\" data-pb-dropzone=\"publicaitonContent-info-tab-metrics\">\n<div class=\"altmetric-embed\" data-badge-popover=\"left\" data-badge-type=\"1\" data-doi=\"10.1002\/sctm.20-0472\" data-hide-no-mentions=\"false\" data-uuid=\"9cfd91e1-3914-0356-9af6-a6d2b7490241\"><a href=\"https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536\" target=\"_self\" rel=\"popover\" data-content=\"&lt;div&gt;    &lt;div style='padding-left: 10px; line-height:18px; border-left: 16px solid #FF0000;'&gt;\n      &lt;a class='link-to-altmetric-details-tab' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536&amp;tab=news'&gt;\n          Picked up by &lt;b&gt;89&lt;\/b&gt; news outlets\n      &lt;\/a&gt;\n    &lt;\/div&gt;\n    &lt;div style='padding-left: 10px; line-height:18px; border-left: 16px solid #ffd140;'&gt;\n      &lt;a class='link-to-altmetric-details-tab' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536&amp;tab=blogs'&gt;\n          Blogged by &lt;b&gt;6&lt;\/b&gt;\n      &lt;\/a&gt;\n    &lt;\/div&gt;\n    &lt;div style='padding-left: 10px; line-height:18px; border-left: 16px solid #74CFED;'&gt;\n      &lt;a class='link-to-altmetric-details-tab' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536&amp;tab=twitter'&gt;\n          Tweeted by &lt;b&gt;67&lt;\/b&gt;\n      &lt;\/a&gt;\n    &lt;\/div&gt;\n    &lt;div style='padding-left: 10px; line-height:18px; border-left: 16px solid #2445bd;'&gt;\n      &lt;a class='link-to-altmetric-details-tab' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536&amp;tab=facebook'&gt;\n          On &lt;b&gt;2&lt;\/b&gt; Facebook pages\n      &lt;\/a&gt;\n    &lt;\/div&gt;\n    &lt;div style='padding-left: 10px; line-height:18px; border-left: 16px solid #D5E8F0;'&gt;\n      &lt;a class='link-to-altmetric-details-tab' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536&amp;tab=reddit'&gt;\n          Reddited by &lt;b&gt;2&lt;\/b&gt;\n      &lt;\/a&gt;\n    &lt;\/div&gt;\n\n    &lt;div class='altmetric-embed readers' style='margin-top: 10px;'&gt;\n          &lt;div class='altmetric-embed tip_mendeley'\n               style='padding-left: 10px; line-height:18px; border-left: 16px solid #A60000;'&gt;\n              &lt;b&gt;34&lt;\/b&gt; readers on Mendeley\n          &lt;\/div&gt;\n    &lt;\/div&gt;\n    &lt;div style='margin-top: 10px; text-align: center;'&gt;\n        &lt;a class='altmetric_details' target='_self' href='https:\/\/www.altmetric.com\/details.php?domain=stemcellsjournals.onlinelibrary.wiley.com&amp;citation_id=97132536'&gt;\n            See more details\n        &lt;\/a&gt;\n    &lt;\/div&gt;\n&lt;\/div&gt;\" data-badge-popover=\"left\"> <img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/d1uo4w7k31k5mn.cloudfront.net\/v1\/746.png\" alt=\"Article has an altmetric score of 746\" width=\"110\" height=\"20\" \/> <\/a><\/div>\n<\/div>\n<\/div>\n<\/section>\n<section class=\"details\">\n<h3 class=\"info-header\">Details<\/h3>\n<p class=\"copyright\">\u00a9 2021 The Authors. <span class=\"smallCaps\">STEM CELLS TRANSLATIONAL MEDICINE<\/span> published by Wiley Periodicals LLC on behalf of AlphaMed Press<\/p>\n<p>This is an open access article under the terms of the <a title=\"Link to external resource\" href=\"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/\" target=\"_blank\" rel=\"noopener noreferrer\">Creative Commons Attribution\u2010NonCommercial\u2010NoDerivs<\/a> License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non\u2010commercial and no modifications or adaptations are made.<\/p>\n<ul class=\"cross-mark rlist\">\n<li><a data-target=\"crossmark\"><img decoding=\"async\" src=\"https:\/\/crossmark-cdn.crossref.org\/widget\/v2.0\/logos\/CROSSMARK_Color_horizontal.svg\" width=\"150\" \/><\/a><\/li>\n<\/ul>\n<\/section>\n<section class=\"funding-information\">\n<h3 class=\"info-header\">Research funding<\/h3>\n<ul class=\"unordered-list\">\n<li>National Center for Advancing Translational Sciences. Grant Numbers: UL1TR002736, UL1TR000460<\/li>\n<li>Ugo Colombo<\/li>\n<li>Simkins Family Foundation<\/li>\n<li>Fondazione Silvio Tronchetti Provera<\/li>\n<li>Barilla Group and Family<\/li>\n<li>Diabetes Research Institute Foundation (DRIF)<\/li>\n<li>The Cure Alliance<\/li>\n<li>North America&#8217;s Building Trades Unions (NABTU)<\/li>\n<\/ul>\n<\/section>\n<section class=\"keywords\">\n<h3 class=\"info-header\">Keywords<\/h3>\n<ul class=\"rlist rlist--inline\">\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=cell transplantation\">cell transplantation<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=cellular therapy\">cellular therapy<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=clinical trials\">clinical trials<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=mesenchymal stem cells\">mesenchymal stem cells<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=respiratory tract\">respiratory tract<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=transplantation\">transplantation<\/a><\/li>\n<li><a class=\"badge-type\" href=\"https:\/\/stemcellsjournals.onlinelibrary.wiley.com\/action\/doSearch?field1=Keyword&amp;text1=umbilical cord\">umbilical cord<\/a><\/li>\n<\/ul>\n<\/section>\n<section class=\"publication-history\">\n<h3 class=\"info-header\">Publication History<\/h3>\n<ul class=\"rlist\">\n<li><label>Version of Record online: <\/label>05 January 2021<\/li>\n<li><label>Manuscript accepted: <\/label>06 December 2020<\/li>\n<li><label>Manuscript revised: <\/label>22 November 2020<\/li>\n<li><label>Manuscript received: <\/label>23 October 2020<\/li>\n<\/ul>\n<\/section>\n<\/section>\n<\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Human Clinical Articles Open Access Umbilical cord mesenchymal stem cells for COVID\u201019 acute respiratory distress syndrome: A double\u2010blind, phase 1\/2a, randomized controlled trial Sections PDF Tools Share Abstract Acute respiratory distress syndrome (ARDS) in COVID\u201019 is associated with high mortality. &hellip; <a class=\"more-link\" href=\"http:\/\/mydiabeticsoul.com\/?p=1675\">Continue reading <span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1675","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"_links":{"self":[{"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/posts\/1675","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1675"}],"version-history":[{"count":1,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/posts\/1675\/revisions"}],"predecessor-version":[{"id":1676,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=\/wp\/v2\/posts\/1675\/revisions\/1676"}],"wp:attachment":[{"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1675"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1675"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/mydiabeticsoul.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1675"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}